Virtual reality and neuropsychological assessment: The reliability of a virtual kitchen to assess daily-life activities in victims of traumatic brain injury.

Traumatic brain injury (TBI) causes impairments affecting instrumental activities of daily living (IADL). However, few studies have considered virtual reality as an ecologically valid tool for the assessment of IADL in patients who have sustained a TBI. The main objective of the present study was to examine the use of the Nonimmersive Virtual Coffee Task (NI-VCT) for IADL assessment in patients with TBI. We analyzed the performance of 19 adults suffering from TBI and 19 healthy controls (HCs) in the real and virtual tasks of making coffee with a coffee machine, as well as in global IQ and executive functions. Patients performed worse than HCs on both real and virtual tasks and on all tests of executive functions. Correlation analyses revealed that NI-VCT scores were related to scores on the real task. Moreover, regression analyses demonstrated that performance on NI-VCT matched real-task performance. Our results support the idea that the virtual kitchen is a valid tool for IADL assessment in patients who have sustained a TBI

Detecting everyday action deficits in Alzheimer’s disease using a non-immersive virtual reality kitchen

Alzheimer’s disease (AD) causes impairments affecting instrumental activities of daily living (IADL). Transdisciplinary research in neuropsychology and virtual reality has fostered the development of ecologically valid virtual tools for the assessment of IADL, using simulations of real life activities. Few studies have examined the benefits of this approach in AD patients. Our aim was to examine the utility of a non-immersive virtual coffee task (NI-VCT) for assessment of IADL in these patients. We focus on the assessment results obtained from a group of 24 AD patients on a task designed to assess their ability to prepare a virtual cup of coffee, using a virtual coffee machine. We compared performance on the virtual task to an identical daily living task involving the actual preparation of a cup of coffee, as well as to global cognitive, executive, and caregiver-reported IADL functioning. Relative to 32 comparable, healthy elderly (HE) controls, AD patients performed worse than HE controls on all tasks. Correlation analyses revealed that NI-VCT measures were related to all other neuropsychological measures. Moreover, regression analyses demonstrated that performance on the NI-VCT predicted actual task performance and caregiver-reported IADL functioning. Our results provide initial support for the utility of our virtual kitchen for assessment of IADL in AD patients. (JINS, 2014, 20, 1–10

Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup

The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup conducted a systematic literature review using a standardized process to develop evidence-based recommendations on the use of extracorporeal treatment (ECTR) in patients with phenytoin poisoning. The authors reviewed all articles, extracted data, summarized findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 51 articles met the inclusion criteria. Only case reports, case series, and pharmacokinetic studies were identified, yielding a very low quality of evidence. Clinical data from 31 patients and toxicokinetic grading from 46 patients were abstracted. The workgroup concluded that phenytoin is moderately dialyzable (level of evidence = C) despite its high protein binding and made the following recommendations. ECTR would be reasonable in select cases of severe phenytoin poisoning (neutral recommendation, 3D). ECTR is suggested if prolonged coma is present or expected (graded 2D) and it would be reasonable if prolonged incapacitating ataxia is present or expected (graded 3D). If ECTR is used, it should be discontinued when clinical improvement is apparent (graded 1D). The preferred ECTR modality in phenytoin poisoning is intermittent hemodialysis (graded 1D), but hemoperfusion is an acceptable alternative if hemodialysis is not available (graded 1D). In summary, phenytoin appears to be amenable to extracorporeal removal. However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning

The Value of a virtual Kitchen to assess the activities of Daily life in Alzheimer Disease

Patients with Alzheimer\u27s disease (AD patients) experience difficulties in everyday life activities that effect independence. These difficulties can be tested using virtual reality (VR) environments that simulate real life situations. The purpose of this study was to examine the value of a virtual kitchen as an assessment tool of everyday life activities in AD patients. We focus on the assessment results obtained in a group of AD patients on a virtual kitchen designed to assess their ability to prepare a virtual cup of coffee using a virtual coffee machine. An identical real daily living task was tested. Twenty-four AD patients were matched to 32 healthy elderly controls. Significant differences in performance between research and control groups were detected on the virtual and the real tasks, with the research group performing worse. In addition, regression analyses revealed that the number of errors in the virtual test was the best predictor for the real assessment and the Instrumental Activities of Daily Living score. This provides initial support for the sensitivity and the ecological validity of the virtual kitchen as an assessment tool of everyday life activities in AD patient

Determination of vancomycin and gentamicin clearance in an in vitro, closed loop dialysis system

Background\ud The purpose of this study was to evaluate the feasibility of utilizing an in-vitro, closed loop hemodialysis system as a method to assess drug clearance. Secondarily, this study tested the influence of variables (blood flow rate, dialysate flow rate, and type of filter) in the hemodialysis procedure on the clearance of vancomycin and gentamicin.\ud \ud Methods\ud An in-vitro, closed loop hemodialysis system was constructed. The vancomycin (30 mg/L) and gentamicin (25 mg/L) were added to a simulated blood system (SBS). Four conditions (C1-C4) were tested by defining the filter (Polyflux 170H or F180) and the blood and dialysate flow rates (BFR and DFR). All hemodialysis sessions were 3 hours in length and each condition was completed in duplicate. Dialysate effluent was collected in a 50 gallon polyethylene drum. Samples were collected (in duplicate) from the SBS and the dialysate effluent at baseline and at the end of the hemodialysis session. Samples were analyzed for vancomycin and gentamicin with an ultrahigh performance liquid chromatography/tandem mass spectrometry method.\ud \ud Results\ud A total of eight 3-hour hemodialysis sessions were conducted. For all tested conditions (C1-C4), vancomycin was undetectable in the SBS at the end of dialysis. However, total vancomycin recovery in the dialysis effluent was 85±18%, suggesting that up to 15% may have adsorbed to the dialysis filter or tubing. Gentamicin clearance from SBS was >98% in all tested conditions. Average gentamicin recovery in the dialysate effluent was 99±15%.\ud \ud Conclusion\ud Both vancomycin and gentamicin were readily removed by high-flux hemodialysis under all conditions studied. No significant differences in drug clearance were observed between conditions used in this in vitro study. The clinical implications of changing these hemodialysis parameters are unknown

Redox Control Of Allergic Airway Disease: Impact Of Glutaredoxin-1 On Epithelial Driven Inflammation And Allergen-Induced Airway Remodeling

Asthma is a multi-faceted chronic inflammatory disease accompanied by loss of airway epithelial integrity leading to remodeling of the airways. Perturbations to the lung redox environment, including alterations in glutathione (GSH) content, have been reported in asthma. GSH can be conjugated to protein cysteines, controlling protein function in an oxidant-dependent process known as protein S-glutathionylation (PSSG). The thioltransferase, glutaredoxin-1 (Glrx1), deglutathionylates proteins under physiological conditions, restoring sulfhydryl groups of target proteins. Glrx1 is emerging as a critical player in settings of allergic airway disease, but its function in regulating epithelial cell responses to asthma-relevant cytokines has not been examined. Furthermore, the role of Glrx1 in controlling the extent of airway remodeling in response to house dust mite (HDM) in vivo is still not well understood. Interleukin-17A (IL-17A) is a potent cytokine that stimulates epithelial cells to produce pro-inflammatory mediators, in part by activating the nuclear factor kappaB (NF-κB) pathway, a key regulator of inflammation. We demonstrate that interleukin-17A (IL-17A) induces rapid activation of both classical and alternative NF-κB, while simultaneously resulting in protein oxidation and PSSG. In particular, we show IL 17A induces S-glutathionylation of RelA (RelA-SSG) and IKKα (IKKα-SSG), which is enhanced following siRNA-mediated knockdown of Glrx1. We also demonstrate that absence of Glrx1 leads to increased nuclear content of RelA and RelB and enhanced production of NF-κB-driven pro-inflammatory genes, KC and CCL20 while decreasing IL-6 expression. Finally, we show that siRNA-mediated knockdown of IKKα attenuates nuclear RelA and RelB and dampens pro-inflammatory gene production. Together, these data indicate a crucial role for the Glrx1/PSSG axis in controlling RelA-SSG, IKKα-SSG and epithelial cell responsiveness to IL-17A. Mice lacking Glrx1 were previously shown to display enhanced resolution of allergic airway disease induced by ovalbumin (Ova) challenge. In this study, we determined the role of Glrx1 in a HDM model of allergic airway disease. Wild type (WT) mice and Glrx1 deficient (Glrx1-/-) mice demonstrated similar total lung cell counts, but Glrx1-/- mice displayed fewer neutrophils than WT mice. Conversely, mice overexpressing Glrx1 specifically in CCSP positive cells in the lung (Epi-Glrx1) showed attenuated total lung cell counts and lung eosinophils compared to control mice. Immunohistological analysis of remodeling markers revealed that Glrx1-/- mice displayed increased HDM-induced mucus metaplasia, α smooth muscle actin (αSMA) positivity and collagen staining compared to WT mice. Evaluation of total lung collagen showed that Glrx1-/- mice had significantly higher collagen content compared to WT mice. In Epi-Glrx1 mice, attenuation of mucus metaplasia, αSMA content and collagen staining was observed compared to control mice. Furthermore, Epi-Glrx1 mice also demonstrated significantly impaired collagen production compared to control mice. We also demonstrate that Glrx1 absence results in decreased expression of the epithelial cell marker, E-cadherin, and increased expression of αSMA, a mesenchymal marker. Together, these studies demonstrate a critical role for Glrx1 in controlling epithelial cell responses to IL-17A and in mediating in vivo collagen production in response to chronic allergen exposure

Bond percolation on isoradial graphs: criticality and universality

In an investigation of percolation on isoradial graphs, we prove the criticality of canonical bond percolation on isoradial embeddings of planar graphs, thus extending celebrated earlier results for homogeneous and inhomogeneous square, triangular, and other lattices. This is achieved via the star-triangle transformation, by transporting the box-crossing property across the family of isoradial graphs. As a consequence, we obtain the universality of these models at the critical point, in the sense that the one-arm and 2j-alternating-arm critical exponents (and therefore also the connectivity and volume exponents) are constant across the family of such percolation processes. The isoradial graphs in question are those that satisfy certain weak conditions on their embedding and on their track system. This class of graphs includes, for example, isoradial embeddings of periodic graphs, and graphs derived from rhombic Penrose tilings.Comment: In v2: extended title, and small changes in the tex

Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 5′ untranslated region of the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP). Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC) lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid in the discovery of novel therapeutics for FXS and other autism-spectrum disorders sharing common pathophysiology.FRAXA Research FoundationHarvard Stem Cell Institute (seed grant)Stanley Medical Research InstituteNational Institute of Mental Health (U.S.) (grant #R33MH087896